The present application is directed to novel anti-diabetic compounds formed by chemically coupling diphenylethylene compounds with thiazolidine or oxazolidine intermediates. These compounds are effective in lowering blood glucose, serum insulin and triglyceride levels in animal models of type II diabetes. However, surprisingly, these compounds increase the leptin level and have no liver toxicity.
The causes of type I and type II diabetes are yet unknown, although both genetics and environment seem to be the factors. Insulin dependent type I and non-insulin type II are the types which are known. Type I is an autonomic immune disease in which the responsible auto antigen is still unknown. Patients of type I need to take insulin intravenously to survive. However, type II diabetes, the more common form, is a metabolic disorder resulting from the body's inability to make a sufficient amount of insulin or to properly use the insulin that is produced. Insulin secretion and insulin resistance are considered the major defects, however, the precise genetic factors involved in the mechanism remain unknown.
Patients with diabetes usually have one or more of the following defects:
Less production of insulin by the pancreas; PA1 Over secretion of glucose by the liver; PA1 Independent of the glucose uptake by the skeletal muscles; PA1 Defects in glucose transporters, desensitization of insulin receptors; and PA1 Defects in the metabolic breakdown of polysaccharides. PA1 n, m, q and r are independently integers from zero to 4; p and s are independently integers from zero to 5; a, b and c are double bonds which may be present or absent; PA1 R, R' and R" are independently H, C.sub.1 -C.sub.20 linear or branched alkyl, C.sub.2 -C.sub.20 linear or branched alkenyl, --CO.sub.2 H, --CO.sub.2 R'", --NH.sub.2, --NHR'", --NR.sub.2 '", --OH, --OR'", halo, substituted C.sub.1 -C.sub.20 linear or branched alkyl or substituted C.sub.2 -C.sub.20 linear or branched alkenyl, wherein R'" is C.sub.1 -C.sub.20 linear or branched alkyl or linear or branched alkenyl; PA1 A, A' and A" are independently H, C.sub.1 -C.sub.20 acylamino; PA1 B, B' and B" are independently H; PA1 X, X' are independently --NH, --NR'", O or S.
Other than the intravenous application of insulin, there are about 4 classes of oral hypoglycemic agents used.
Approved Mechanisms of Class Drugs Action Limitations sulfonylurea 4 (1st acts on dev. of generation) pancreas to resistance and release more 2 (2nd insulin generation) biguanides metformin reduces liver glucose problems, secretion by lactic liver; acidosis improves insulin sensitivity alpha- acarbose interferes only useful glucosidase with at post- inhibitor digestive pradiandio process; level reduces glucose absorption thiazolidin troglitazone reduces "add-on" e-dione insulin with resistancy insulin; not useful for people with heart and liver disease
As is apparent from the above table, each of the current agents available for use in treatment of diabetes has certain disadvantages. Accordingly, there is a continuing interest in the identification and development of new agents, particularly, water soluble agents which can be orally administered, for the use of treatment of diabetes.